Enantioselective total synthesis of octalactin a using asymmetric aldol reactions and a rapid lactonization to form a medium-sized ring

Article abstract of DOI:10.1002/chem.200500417

Octalactin A, an antitumor agent containing an eight-memhered lactone moiety, has been stereoselectively prepared by means of enantioselective aldol reactions of selected silyl enolates with achiral aldehydes, promoted by a chiral Sn¹¹ complex.

Full text of DOI:10.1002/chem.200500417

FULL PAPER
DOI: 10.1002/chem.200500417
Enantioselective Total Synthesis of Octalactin A UsingAsymmetric Aldol
Reactions and a Rapid Lactonization To Form a Medium-Sized Ring
Isamu Shiina,* Minako Hashizume, Yu-suke Yamai, Hiromi Oshiumi, Takahisa Shimazaki,
Yu-ji Takasuna, and Ryoutarou Ibuka[a]
Abstract: Octalactin A, an antitumor
agent containing an eight-membered
lactone moiety, has been stereoselec-
tively prepared by means of enantiose-
lective aldol reactions of selected silyl
enolates with achiral aldehydes, pro-
moted by a chiral SnII complex. The
medium-sized lactone part was effec-
tively constructed by way of a new and
rapid mixed-anhydride lactonization
using 2-methyl-6-nitrobenzoic anhy-
dride (MNBA) with a catalytic amount
of 4-(dimethylamino)pyridine (DMAP)
or 4-(dimethylamino)pyridine 1-oxide
(DMAPO). The use of only 5 mol% of
DMAP or 2 mol% of DMAPO rapidly
promoted formation of the medium-
sized ring of the octalactin, demon-
strating the remarkable efficiency of
the new lactonization protocol.
Keywords: aldol reaction · enantio-
selectivity · octalactin A · rapid lac-
tonization · total synthesis
Introduction
the total synthesis of the natural octalactins from d- and l-
3-hydroxy-2-methylpropionic acids by Buszek et al.[3] and
the total synthesis of the ent-octalactins (antipodes) from
(+)-citronellic acid by McWilliams and Clardy.[4] In 2000,
Buszek et al. synthesized octalactins by an alternative ap-
proach, which involved the formation of the eight-mem-
bered lactone moiety by olefin metathesis.[5] Also, Holmes
et al. quite recently accomplished the total synthesis of 1
and 2 utilizing their original rearrangement reaction to form
the medium-sized ring of the octalactins.[6] Some formal syn-
theses and related synthetic
Octalactin A (1), a cytotoxic compound, was isolated in
1991 from the marine bacterium Streptomyces sp. together
with a related eight-membered lactone molecule, octalactin
B (2).[1] The octalactins consist of highly oxidized medium-
sized ring frameworks, and the synthesis of these peculiar
and complex structures has become one of the most interest-
ing topics in organic chemistry.[2] The absolute configura-
tions of 1 and 2 were independently determined in 1994 by
studies of octalactins have also
been reported.[7]
In 1998, the total synthesis of
cephalosporolide
D
(3), an
eight-membered lactone similar
to the octalactins, was attained
by our group.[8] The exact ste-
reochemistry of this molecule
was determined by the utiliza-
tion of a chiral induction technology, which provides optical-
ly active compounds (Scheme 1); that is, both asymmetric
carbon atoms were constructed by the asymmetric aldol re-
actions of an enol silyl ether with aldehydes in the presence
of a chiral catalyst.[9,10] Furthermore, the desired eight-mem-
bered lactone moiety was obtained by the efficient cycliza-
tion of the seco acid by a novel mixed anhydride method
using (4-trifluoromethyl)benzoic anhydride (TFBA) with
Hf(OTf)4.[11,12]
[a] Prof. Dr. I. Shiina, M. Hashizume, Y. Yamai, H. Oshiumi,
T. Shimazaki, Y. Takasuna, R. Ibuka
Department of Applied Chemistry
Faculty of Science, Tokyo University of Science
Kagurazaka, Shinjuku-ku
Tokyo 162–8601 (Japan)
Fax : (+81)3-3260-5609
E-mail: shiina@ch.kagu.tus.ac.jp
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
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to
1 and/or 2 have also been described in previous
papers,[3,4] allylic alcohol 4 was determined to be our target
precursor for the synthesis of 1 and 2 (Scheme 2). It is also
assumed that 4 could be prepared by the nucleophilic addi-
tion of a metallic species, generated from 6, to aldehyde 5
according to literature methods.[3,4] Synthesis of the eight-
membered lactone part 7 was planned by starting from the
linear compound 8, which could be obtained from the two
segments 9 and 10. Preparation of both of the optically
active anti-b-hydroxy-a-methyl units 9 and 10 was to be ach-
ieved by the enantioselective aldol addition of a tetrasubsti-
tuted KSA to an aldehyde, followed by successive stereose-
lective defunctionalization. Aldol 12 was chosen as a precur-
sor to the siloxyalkyne 11, which could be converted to the
side chain 6.[3]
Scheme 1. Stereoselective total synthesis of cephalosporolide D.
In our continuous efforts directed towards the synthesis of
natural compounds containing eight-membered rings,[8,13] the
total synthesis of 1 and 2 was planned using a similar strat-
egy.[14] First, we postulated that an optically active seco acid
of the eight-membered lactone could be constructed through
the enantioselective aldol reactions of a ketene silyl acetal
(KSA) with aldehydes promoted by Sn(OTf)2 coordinated
to a chiral diamine ligand. Second, effective lactonization
using 2-methyl-6-nitrobenzoic anhydride (MNBA) with
basic catalysts might then be applicable for producing the
eight-membered lactone part of the octalactins.[15]
Results and Discussion
Synthesis of aldol-type fragments by desulfurization: The
optically active aldol syn-16 was synthesized with high ste-
reoselectivity by the asymmetric aldol reaction of tetrasub-
stituted KSA 13, derived from ethyl 2-methylthiopropa-
noate, with b-siloxyaldehyde 14. The catalyst for the reac-
tion was a chiral Lewis acid consisting of Sn(OTf)2, chiral di-
amine, and nBu3SnF (Scheme 3). The enantiomeric excess
(ee) of syn-16 was determined by HPLC analysis of the cor-
responding tert-butyldiphenylsilyl (TBDPS) ether generated
from syn-16, as shown in the
Because synthetic intermediates similar to 4 have already
been prepared, and the transformations of these compounds
Supporting Information. Direct
acetalization of syn-16 with
benzaldehyde diethyl acetal in
the presence of p-toluenesul-
fonic acid afforded
a cyclic
compound 17. Desulfurization
of 17 with nBu3SnH was carried
out according to a protocol,
similar to that developed by
Guindon et al., giving the de-
sired anti-b-hydroxy-a-methyl
unit 18 with high diastereose-
lectivity.[16,17] The ester group
was reduced by LiAlH4 and
halogenation of the resulting
primary alcohol afforded the
corresponding iodoalkane. Suc-
cessive reductive cleavage of
the benzylidene acetal part and
protection of the primary alco-
hol produced the desired right-
hand segment 9, which was fur-
ther converted to the phospho-
nium salt 19 by a conventional
method.
The left-hand segment 10 was
also prepared, as illustrated by
Scheme 4. The optically active
Scheme 2. Retrosynthesis of octalactins from optically active linear compounds.
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Total Synthesis of Octalactin A
FULL PAPER
Scheme 3. Reagents and conditions: a) chiral SnII complex 15, nBu3SnF,
CH2Cl2, À788C (64%, syn/anti 93:7, 87% ee for syn); b) PhCH(OEt)2,
TsOH, CH2Cl2, RT (77% from syn); c) nBu3SnH, azobisisobutyronitrile
(AIBN), benzene, reflux (quant, anti/syn 89:11); d) i) LiAlH4, THF, 08C
(98% from anti); ii) I2, Ph3P, imidazole, benzene, RT (94%); iii) diisobu-
tylaluminium hydride (DIBAL), CH2Cl2, 08C (94%); iv) TBSCl, imida-
zole, DMF, RT (96%); e) Ph3P, iPr2NEt, CH3CN, reflux (84%).
Scheme 5. Reagents and conditions: a) H2SO4, EtOH, reflux (67%);
b) LDA, MeI, THF, À788C (74%, anti/syn 92:8); c) BH3·THF, reflux
(96%); d) PMPCH(OMe)2, CSA, CH2Cl2, RT (66% for ent-24); PhCH-
(OMe)2, TsOH, CH2Cl2, RT (82% for 28); e) (COCl)2, dimethylsulfoxide
(DMSO), Et3N, CH2Cl2, À508C to RT (98%); f) BrÀPh3P+CH3, KHMDS,
THF, toluene, À78 to 08C (96%); g) 9-BBN, THF, 08C; then H2O, 3 m
NaOH, 35% H2O2, RT (99%); h) TBSCl, imidazole, DMF, RT (87% for
32); TIPSCl, imidazole, DMF, RT (97% for 33); i) BH3·SMe2,
ZnEt2·OEt2, THF, 508C (86% for 34); DIBAL, CH2Cl2, 08C (90% for
35); j) I2, Ph3P, imidazole, benzene, RT (90% for 9; 95% for 36).
of the sense of optical rotation of 24 (Scheme 4) and ent-24
(Scheme 5), it was revealed that the absolute stereochemis-
try of C-2 in 24 and 10 was R. In addition, 27 was treated
with benzaldehyde dimethyl acetal to produce the cyclic
compound 28, and a conventional one-carbon elongation via
Scheme 4. Reagents and conditions: a) chiral SnII complex ent-15,
nBu3SnF, CH2Cl2, À788C (51%, syn/anti 81:19, 83% ee for syn); b) i) tet-
rabutylammonium fluoride (TBAF), AcOH, THF, 08C (91% from syn);
ii) Me2C(OMe)2, MsOH, CH2Cl2, RT (85%); c) nBu3SnH, AIBN, ben-
zene, reflux (93%, anti/syn 88:12); d) i) LiAlH4, THF, 08C (82% from
anti); ii) pyridinium p-toluene sulfonate (PPTS), MeOH, reflux;
iii) PMPCH(OMe)2 (PMP=4-methoxyphenyl), PPTS, CH2Cl2, RT (86%,
two steps); e) PhSNHtBu, NCS, K2CO3, MS 4Š, CH2Cl2, RT (99%).
aldol syn-21, generated from KSA 13 and a-siloxyaldehyde
20, was transformed to the cyclic acetal 22, which subse-
quently underwent smooth diastereoselective desulfurization
to preferentially yield the desired anti-b-hydroxy-a-methyl
unit 23. Successive reduction of the ester group, formation
of p-methoxybenzylidene acetal, and oxidation of the inter-
mediary primary alcohol produced the corresponding opti-
cally active aldehyde 10.[18]
The absolute stereochemistry of 10 and 19 was deter-
mined as follows (Scheme 5). (S)-Malic acid was converted
to the corresponding methylated diethyl ester 26 via 25 ac-
cording Seebachꢁs procedure.[19] Reduction of both ester
parts and successive protection of the resulting triol 27 by p-
methoxybenzylidene acetal afforded ent-24. By comparison
Scheme 6. Reagents and conditions: a) chiral SnII complex 15, nBu3SnF,
CH2Cl2, À788C (57%, syn/anti 75:25, 95% ee for syn); b) nBu2BOTf,
iPr2NEt, CH2Cl2, 08C; then nBu3SnH, Et3B, À788C (84%, anti/syn
90:10); c) i) BnOC(CCl3)=NH, TfOH, Et2O, 08C (85%); ii) LiAlH4,
THF, 08C (98% from anti); d) I2, Ph3P, imidazole, benzene, RT (95%);
e) Ph3P, iPr2NEt, CH3CN, reflux (quant).
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29 and 30 afforded primary al-
cohol 31 as preliminarily re-
ported by the Yamamura
group.[20] Protection of the hy-
droxyl group with tert-butyldi-
methylsilyl (TBS) or triisopro-
pylsilyl (TIPS) ether, followed
by reductive cleavage of the
benzylidene acetal, yielded the
five-carbon units 34 and 35, re-
spectively. Iodoalkanes 9 and
36 were prepared from 34 and
35 by treatment with I2 and
Ph3P, and the product
9
(Scheme 5) was identified by
comparison with the former
compound 9 derived from aldol
syn-16 (Scheme 3); therefore, it
can be deduced that C-3 in
compounds 9 and 19 also has
an R configuration.
Scheme 8. Reagents and conditions: a) NaHMDS, toluene, À788C to RT (83% for 43; 88% for 44);
b) i) DIBAL, CH2Cl2, À5 or À108C (79% from 43; 86% from 44); ii) TBDPSCl, Et3N, DMAP, CH2Cl2, RT
(91% for 45; 82% for 46); c) 1m HCl, THF, RT (99% from 45; 95% from 46); d) i) DMP, CH2Cl2, RT; ii)
NaClO2, NaH2PO4, 2-methyl-2-butene, tBuOH, H2O, RT (94%, two steps) or TEMPO, NaClO2, NaClO,
buffer, H2O, CH3CN, 358C (96%); e) i) CAN, H2O, CH3CN, 08C (94%); ii) H2, 10% Pd/C, Et3N, MeOH, RT
(87%).
Synthesis of aldol-type frag-
Table 1. Synthesis of the eight-membered lactone 7: Application of the
S-pyridyl ester method.
ments by deselenization: Recently, Guindon et al. reported
direct deselenization of C-2 selenylated aldols to afford the
corresponding anti-aldol units.[21] These successful results
prompted us to create an alternative pathway for the gener-
ation of the optically active right and left-hand segments 40
and 10 utilizing asymmetric aldol reactions and sequential
stereoselective deselenization (Schemes 6 and 7). KSA 37
was easily generated from methyl 2-methylselenopropanoate
by the general procedure (see Supporting Information). In
the presence of chiral SnII complex 15, the asymmetric aldol
reaction between KSA 37 and aldehyde 14 proceeded
smoothly to afford the desired aldol syn-38 in good yield
and with high enantioselectivity. The conversion of syn-38 to
the corresponding aldol anti-39 was successfully carried out
Entry
Time [h]
Yield [%][a]
1
2
96
48
13
96
63
51
5
3
4[b]
0
[a] Isolated yield. [b] The reaction was carried out at room temperature.
by the literature method,[21c] and transformation of 39 to the
phosphonium salt 40 via 35 and 36 was also achieved with-
out difficulty (Scheme 6). As compound 40 was prepared via
compound 36 (stereochemistry previously determined,
Scheme 5), the absolute stereochemistry of C-3 in 40 was
deduced to be R.
Furthermore, the aldol reaction of aldehyde 20 with KSA
37, promoted by the chiral SnII complex ent-15, produced
the four-carbon unit syn-41 with high enantioselectivity
(Scheme 7).[22] Treatment of syn-41 with nBu2BOTf,
iPr2NEt, and nBu3SnH, effected diastereoselective deseleni-
zation producing aldol anti-42 in good yield. Reduction of
the ester group and protection of the intermediary diol with
a p-methoxybenzylidene group provided alcohol 24, which
was identified by comparison with the former compound 24
synthesized by the route shown in Scheme 4. Thus, an im-
Scheme 7. Reagents and conditions: a) chiral SnII complex ent-15,
nBu3SnF, CH2Cl2, À788C (54%, syn/anti 79:21, 88% ee for syn); b) nBu2-
BOTf, iPr2NEt, CH2Cl2, RT; then nBu3SnH, Et3B, À788C (77%, anti/syn
94:6); c) i) DIBAL, CH2Cl2, 08C (80%); ii) PMPCH(OMe)2, CSA,
CH2Cl2, RT (84% from anti); iii) TBAF, THF, 08C (95%); d) PhSNHtBu,
NCS, K2CO3, MS 4 Š, CH2Cl2, RT (99%).
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Total Synthesis of Octalactin A
FULL PAPER
proved method for the synthesis of the optically active right-
and left-hand segments of the octalactins has been devel-
oped according to our chiral induction technology, which
employs SnII-promoted asymmetric aldol reactions and suc-
cessive diastereoselective deselenization.
bond without removal of the benzyl group.[24] In addition,
the coupling reaction of the left-hand segment 10 with the
alternative right-hand segment 40 produced the nine-carbon
unit 44 in high yield. Disilyl ether 44 was converted to the
synthetic intermediate 47 by using similar methods to those
applied to the synthesis of compounds 43 and 45.
Synthesis of the seco acid of the eight-membered lactone
moiety: The two segments 10 and 19 were coupled in the
presence of sodium hexamethyldisilazide (NaHMDS) to
produce the linear polyoxy compound 43 in good yield
(Scheme 8). Reductive cleavage of the acetal moiety fol-
lowed by protection of the resulting primary alcohol afford-
ed the disilyl ether 45. Deprotection of the TBS group fol-
lowed by either conventional stepwise oxidation of the pri-
mary alcohol 47 or single-step oxidation with 2,2,6,6-tetra-
methylpiperdinyloxy free radical (TEMPO)[23] produced the
corresponding carboxylic acid 48. The desired chiral linear
seco acid 8 was then obtained by deprotection of the p-me-
thoxybenzyl (PMB) group and hydrogenation of the double
Formation of the eight-membered lactone moiety by a sub-
stituted benzoic anhydride method: Buszek et al. reported
the successful lactonization of a similar seco acid, in which
the PMB group replaces the Bn group in 8, by the applica-
tion of the S-pyridyl ester method.[3,25,26] However, it was re-
ported that the cyclization required a high reaction tempera-
ture and a long reaction time (96 h); nevertheless, the reac-
tion was accelerated by AgBF4. In actual fact, our group has
found that the reaction of the S-pyridyl ester of 8 proceeds
sluggishly even under very severe conditions (96 h in reflux-
ing toluene with AgBF4) producing the desired eight-mem-
bered lactone 7 in 63% yield (Table 1, entry 1). From en-
tries 2 and 3, it can be seen that
the yield of 7 decreases when
the reaction time is decreased.
For example, only 5% of the
desired lactone 7 was obtained
under the intensive conditions
Table 2. Synthesis of the eight-membered lactone 7: Application of the benzoic anhydride method.
when
the
reaction
was
quenched after 13 h. Further-
more, it was revealed that the
cyclization of the S-pyridyl
ester of 8 did not take place at
room temperature (entry 4).
Therefore, we decided to devel-
op a new and rapid lactoniza-
tion reaction to produce the
medium-sized lactone backbone
7.
Recently, we reported the ef-
fective use of substituted ben-
zoic anhydrides for the prepara-
tion of carboxylic esters, thio-
esters, and carboxamides under
acidic or basic conditions.[12,15]
As it has already been shown
that MNBA is the best dehy-
drating reagent to produce car-
boxylic esters and macrocyclic
lactones by the promotion of
basic catalysts, the MNBA
method was applied to seco
acid 8 to afford the desired
compound 7 (Table 2).
Entry
Catalyst (equiv)
Base (equiv)
Solvent
Yield [%][a]
1
2
3
4
5
6
7
8
9
10
11
12
13[b]
14[d]
15[d]
16[d]
DMAP (6.0)
DMAP (6.0)
DMAP (0.2)
DMAP (0.1)
DMAP (0.05)
DMAP (0.02)
DMAP (0.01)
DMAPO (0.2)
DMAPO (0.1)
DMAPO (0.05)
DMAPO (0.02)
DMAPO (0.01)
DMAP (6.0)
DMAP (3.5)
DMAP (0.1)
DMAPO (0.1)
-
-
CH2Cl2
toluene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
85
84
80
89
81
47
24
82
Et3N (6.0)
Et3N (6.0)
Et3N (6.0)
Et3N (6.0)
Et3N (6.0)
Et3N (6.0)
Et3N (6.0)
Et3N (6.0)
Et3N (6.0)
Et3N (6.0)
-
90
84
78
50
50[c]
84
-
Et3N (6.0)
Et3N (6.0)
46[e]
28[f]
First,
excess
DMAP
(6.0 equiv) was employed as a
promoter for the cyclization of
8 in the presence of MNBA
(1.3 equiv) in dichloromethane
or toluene at room tempera-
[a] Isolated yield. [b] The reaction was carried out in dichloromethane (100 mm). [c] 16-membered diolide (7-
dimer) was obtained in 32% yield. [d] Benzoic anhydride was used as a coupling reagent instead of MNBA.
[e] The symmetric carboxylic anhydride of 8 and its dibenzoate were obtained in 24% and 13% yield, respec-
tively. [f] The symmetric carboxylic anhydride of 8 was obtained in 22% yield.
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I. Shiina et al.
ture, producing the eight-membered lactone 7 in 85 and
84% yield, respectively (entries 1 and 2). Next, the amount
of the catalyst was gradually decreased as shown in en-
tries 3–7, and it was determined that the use of 5 mol% of
DMAP with excess triethylamine (6.0 equiv) was sufficient
to produce 7 in over 80% yield at room temperature
(entry 5). When the reaction was carried out with less than
5 mol% of DMAP , the yield was considerably lowered (en-
tries 6 and 7).
Scheme 9. Reagents and conditions: a) MNBA, DMAP (10 mol%) or
DMAPO (10 mol%), Et3N, CH2Cl2, RT (89% or 90%); b) i) TBAF,
AcOH, THF, RT (99%); ii) TPAP, NMO, MS 4Š, CH2Cl2, 08C (91%).
Alternatively, it has been observed that DMAPO, an
oxide of DMAP, is quite an effective basic promoter for our
lactonization; therefore, we examined the use of DMAPO
as a catalyst in the cyclization reaction (entries 8–12). In
every case, the desired lactone 7 was obtained in a relatively
greater yield when DMAPO was used as opposed to
DMAP. Furthermore, as shown in entry 11, the use of only
2 mol% of DMAPO afforded the targeted lactone in 78%
yield under very mild reaction conditions (room tempera-
ture) and within a short period of time (13 h).
A 16-membered diolide (7-dimer) was formed as a by-
product (32%) when the lactonization of 8 was carried out
under the concentrated reaction conditions (100mm,
entry 13). Interestingly, a simple benzoic anhydride could
also be used for the preparation of 7 from 8 by promotion
with excess DMAP (entry 14); however, the catalytic reac-
tions of 8 with 10 mol% of DMAP or DMAPO with benzo-
ic anhydride produced the cor-
by McWilliams and Clardy[4] to give the multioxygenated
eight-membered lactone 4, a precursor of the octalactins. A
mixture of diastereomers was oxidized to generate the cor-
responding enone, and successive deprotection of the TBS
and Bn groups afforded octalactin B (2; [a]2D3 =À1248 (c=
0.42 in CHCl3).[28] The final conversion of octalactin B to oc-
talactin A was achieved by using tert-butyl hydroperoxide
(TBHP), according to the literature method.[4] All spectral
data including the optical rotations of synthetic 1 corre-
sponded to those of natural octalactin A ([a]2D6 =À1488
(c=0.20 in CHCl3)).[29]
responding lactone
7 in low
yield (46%, entry 15 and 28%,
entry 16, respectively).
Once formed,
7 was then
converted to the eight-mem-
bered lactone aldehyde 5 by de-
protection of the TBDPS
group, followed by successive
oxidation (Scheme 9).
Preparation of the side chain
and completion of the total syn-
thesis: The side chain 6 was
prepared from an optically
active aldol 12, which was gen-
erated by the asymmetric aldol
reaction of 1-ethylthio-1-(trime-
thylsiloxy)ethene (49) with 2-
methylpropionaldehyde
(50)
(Scheme 10).[9,10] Protection of
12 and successive reduction
using Et3SiH with Pd/C afford-
ed the chiral aldehyde 52.[27]
According to Buszekꢁs synthesis
of the side chain, 52 was trans-
formed into the desired vinyl
iodide 6 via the siloxyalkyne
11.[3] The side chain 6 was final-
ly introduced to the aldehyde 5
Scheme 10. Reagents and conditions: a) chiral SnII complex 15, nBu3SnF, CH2Cl2, À788C (65%, 94% ee) or
chiral SnII complex 51 (20 mol%), CH2Cl2, À788C (48%, 90% ee); b) i) TBSCl, imidazole, DMF, RT (95%);
ii) Et3SiH, 10% Pd/C, acetone, RT (88%); c) i) CBr4, PPh3, CH2Cl2, À78 to 08C (86%); ii) nBuLi, THF,
À788C; then MeI, RT (91%); d) Cp2ZrHCl, benzene, sunlamp, 358C; then I2, 78C (72%, 6/53 70:30); e) 6,
tBuLi, Et2O, À788C; then 5 (49%, a/b=57/43); f) i) tetra-n-propylammonium perruthenate (TPAP), NMO,
MS 4Š, CH2Cl2, 08C (75%); ii) 46% HF, CH3CN, 08C (91%); iii) BBr3, CH2Cl2, À95 to À458C (76%);
by using the method reported g) TBHP, VO(acac)2, CH2Cl2, 5–108C (40% based on 70% conversion).
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Total Synthesis of Octalactin A
FULL PAPER
Conclusion
[1] D. M. Tapiolas, M. Roman, W. Fenical, T. J. Stout, J. Clardy, J. Am.
Chem. Soc. 1991, 113, 4682–4683.
An efficient method for the synthesis of octalactin A and its
intermediates, which include octalactin B, has been estab-
lished by enantioselective aldol reactions and a very effec-
tive lactonization using a substituted benzoic anhydride.
[2] R. D. Norcross, I. Paterson, Chem. Rev. 1995, 95, 2041–2114.
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Through our chiral induction technology,
a systematic
method for providing chiral compounds, from both achiral
silylenolates and aldehydes by enantioselective aldol reac-
tions, has successfully been applied to the preparation of an
optically active linear precursor to the eight-membered lac-
tone and side chain of the octalactins. Furthermore, a new
method for constructing the eight-membered lactone moiety
of the octalactins has been established, that utilizes a rapid
cyclization reaction, promoted by MNBA under the influ-
ence of a catalytic amount of DMAP or DMAPO. This syn-
thetic method would be widely applicable to the creation of
various derivatives of octalactin-type antitumor agents.
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Experimental Section
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General methods, detailed experimental procedures, and the spectroscop-
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Typical experimental procedure for the lactonization reaction: 2-Methyl-
6-nitrobenzoic anhydride (MNBA) was purchased from Tokyo Kasei
Kogyo (TCI, M1439).
An experimental procedure is described for the preparation of lactone 7
usingMNBA with a catalytic amount of DMAP (Table 2, entry 4) : A so-
lution of 8 (53.2 mg, 94.5 mmol) in dichloromethane (1 mL) was added to
a solution of MNBA (42.8 mg, 0.124 mmol), DMAP (1.2 mg, 9.6 mmol),
and triethylamine (58.0 mg, 0.574 mmol) in dichloromethane (46.8 mL) at
room temperature. After the reaction mixture had been stirred for 13 h
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methane (0.64 mL) was added to
a mixture of MNBA (28.7 mg,
83.4 mmol) and DMAP (47.0 mg, 0.385 mmol) at room temperature.
After the reaction mixture had been stirred for 13 h at room tempera-
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The mixture was then extracted with dichloromethane, and the organic
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Acknowledgements
This study was partially supported by a Grant-in-Aid for Scientific Re-
search from the Ministry of Education, Science, Sports, and Culture
(Japan). The author thanks Shin-Etsu Chemical (Japan) for kindly pro-
viding tert-butylchlorodimethylsilane as a bulk sample. The author is also
grateful to Yu-suke Kuramoto, Takashi Katoh and Yuri Komiyama for
their cooperation.
Chem. Eur. J. 2005, 11, 6601 – 6608
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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[28] Compare lit:[1,4] [a]=À1238 (revised); lit:[3] [a]=À1268; lit:[6] [a]=
À1238; lit:[4] [a]=+1328 (enantiomorph).
[29] Compare lit:[1,4] [a]=À1408 (revised); lit:[3] [a]=À1528; lit:[6] [a]=
À1538; lit:[4] [a]=+1418 (enantiomorph).
Received: April 14, 2005
Published online: August 24, 2005
6608
www.chemeurj.org
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2005, 11, 6601 – 6608